Monomeric acrylamide is an industrially important agent which produces central-peripheral distal axonopathy in humans and laboratory animals following repeated exposure. Acrylamide is one of several chemically unrelated environmental toxins which induce occupational and environmental polyneuropathy and is a useful tool for creating and studying models of axonal degeneration seen in human neuronal degenerative disease of unknown etiology. Preliminary data have demonstrated that single and repeated doses of acrylamide cause dramatic reductions in the rate of retrograde axoplasmic transport, the means by which neuron cell bodies are informed of the need to repair axon damage. In addition, single doses of acrylamide markedly attenuate perikaryal markers of repair-associated gene expression following axotomy of peripheral nerve. This study will investigate the hypothesis that acrylamide-induced axonopathy is the result of a diminished capacity to repair non-specific axon damage resulting from covalent binding of acrylamide. (1) Perikaryl responses to axotomy will be utilized as a model system to study the effects of both single and repeated doses of acrylamide (and equimolar N,N'-methylene-bis-acrylamide) on perikaryal repair processes. This will include measurement of a marker of gene expression (ornithine decarboxylase), RNA synthesis, mRNA synthesis, and synthesis of repair-specific proteins. (2) The effect of single and repeated doses of acrylamide (and equimolar N,N'-methylene-bis-acrylamide) on capacity for regeneration will be studied in detail using biochemical and morphologic techniques. (3) To examine the role of altered repair processes in acrylamide-induced axonopathy, repair processes in peripheral segments of bipolar afferent neurons will be stimulted by central-process transection. If decreased repair capacity is involved in the etiology of acrylamide-induced axonopathy, stimulation of repair will markedly delay or attenuate the pathogenesis of axonopathy. (4) In the converse of experiment (3) above, the hypothesis that altered repair is involved in the etiology of acrylamide-induced axonopathy will be tested by determining if pharmacologic blockade of repair responses renders non-neurotoxic N,N'-methylene-bis-acrylamide neurotoxic. Diminished perikaryal repair capacity, in the presence of low-level axon damage, represents a novel mechanism by which toxic agents may alter neuronal function or structure. Additionally, these studies will provide detailed data regarding the means by which neuronal repair responses are initiated and regulated. It is expected that these studies will substantially further our understanding of how neurotoxic agents alter normal neuronal processes to produce axonopathy.